Multiple lines of evidence have linked oxidative stress, tau pathology and neuronal cell cycle re-activation to Alzheimer's disease (AD). While a prevailing idea is that oxidative stress-induced neuronal cell cycle reactivation acts as an upstream trigger for pathological tau phosphorylation, others have identified tau as an inducer of cell cycle abnormalities in both mitotic and postmitotic conditions. In addition, nuclear hypophosphorylated tau has been identified as a key player in the DNA damage response to oxidative stress. Whether and to what extent these observations are causally linked remains unclear. Using immunofluorescence, fluorescence-activated nucleus sorting and single-nucleus sequencing, we report an oxidative stress-associated accumulation of nuclear hypophosphorylated tau in a subpopulation of cycling neurons confined in S phase in AD brains, near amyloid plaques. Tau downregulation in murine neurons revealed an essential role for tau to promote cell cycle progression to S phase and prevent apoptosis in response to oxidative stress. Our results suggest that tau holds oxidative stress-associated cycling neurons in S phase to escape cell death. Together, this study proposes a tau-dependent protective effect of neuronal cell cycle reactivation in AD brains and challenges the current view that the neuronal cell cycle is an early mediator of tau pathology.
Alzheimer Disease , Humans , Mice , Animals , Alzheimer Disease/metabolism , tau Proteins/metabolism , S Phase , Phosphorylation , Oxidative Stress , Neurons/metabolism , Amyloid beta-Peptides/metabolism
Recent reports suggested a role for microtubules in double-strand-DNA break repair. We herein investigated the role of the microtubule-associated protein Tau in radio- and chemotherapy. Noticeably, a lowered expression of Tau in breast cancer cell lines resulted in a significant decrease in mouse-xenograft breast tumor volume after doxorubicin or X-ray treatments. Furthermore, the knockdown of Tau impaired the classical nonhomologous end-joining pathway and led to an improved cellular response to both bleomycin and X-rays. Investigating the mechanism of Tau's protective effect, we found that one of the main mediators of response to double-stranded breaks in DNA, the tumor suppressor p53-binding protein 1 (53BP1), is sequestered in the cytoplasm as a consequence of Tau downregulation. We demonstrated that Tau allows 53BP1 to translocate to the nucleus in response to DNA damage by chaperoning microtubule protein trafficking. Moreover, Tau knockdown chemo-sensitized cancer cells to drugs forming DNA adducts, such as cisplatin and oxaliplatin, and further suggested a general role of Tau in regulating the nuclear trafficking of DNA repair proteins. Altogether, these results suggest that Tau expression in cancer cells may be of interest as a molecular marker for response to DNA-damaging anti-cancer agents. Clinically targeting Tau could sensitize tumors to DNA-damaging treatments.
